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1 Lec 5. 면역조절 II

2 미숙림프구

3 3. 면역증진건강기능식품및효능 1) 고시형건강기능식품 (1) 인삼 : 강장, 면역증강기능, 피로회복의기능성 (2) 홍삼 : 면역력증진및피로회복 (3) 알로에겔 : 면역력증진, 피부건강, 항염증효능, 장건강 (4) 알콕시글리세롤함유상어간유 : 면역증강

4 2) 개별인정형건강기능식품 (1) 금사상황버섯 : 인터페론감마와림프구수증가, 면역기능개선 (2) 게란티바이오-Ge 효모 : 면역글로블린, 항체형성효능 (3)L-글루타민 : 림프구양증가, 감염발생감소 (4)HemoHIM 당귀등혼합추출물 : 림프구의활성증가, NK 세포활성, 사이토카인증가

6 제2절항염증및항알레르기 1. 염증및알레르기 1) 염증 1 외부자극에의해손상된생체조직을복구하는면역반응 히스타민 : 손상된조직부위에혈액과림프액공급 킨니스 : 근수축이완으로혈액의운반원활 프로스타글란딘 : 백혈구에서합성되어통증과열발생 2 염증반응의개요 염증유도물질 세포내감지센서 매개체 염증반응이일어나는조직

8 3백혈구의작용 조직손상부위로이동하여염증반응 식세포작용 : 외부의세균및박테리아제거 염증성매개체 (inflammatory mediators) 분비 만성염증 : 단핵세포 (monocyte), 림프구 급성염증 : 과립성백혈구 (granulocytes) Cytokine, chemokine 에의해백혈구와내피세포간의결합활성화 최하부막 (basement membrane) 을뚫고이동하여염증조직으로의침투

9 INITIATORS OF INFLAMMATION Microbial specific exotoxins endotoxins (bacterial, viral, fungal, protozoan) Tissue injury/death Lack of oxygen /nutrients (ischemia) Trauma UV/ionizing radiation, burns Irritant/corrosive chemicals (acids, alkalis,oxidizers) Hypersensitivity immunological responsiveness.. Auto-antibodies attack tissue causes excessive reaction which damages tissues.

10 INFLAMMATION: Cellular elements Inflammatory process is largely defined by products released from local cells which are attracted to the area of inflammation and which become activated What/Which are these cells?

11 INFLAMMATION: Cellular elements Mast cells. Innate immune cells, Tissue-resident Close contact with arterioles and venules. Degranulated by tissue damage, infections or crosslinked IgE Granules contain a variety of active factors

12 INFLAMMATION: Cellular elements Monocytes: Macrophages (tissue specific) or dendritic cells (lymphoid tissue). Macrophages Resident cells Circulate as monocytes and reach site of injury within hrs. Activated by cytokines (TNFa), lipidic acids (prostaglandins / leukotrienes), endotoxins (TOL-r), and other products of inflammation. Dynamic properties..filpodia/active particle engulfment Present though out body. Microglia, Kupffer cells, sinus histiocytes, alveolar macrophages, etc.

Lymphocytes. Antigen-experienced T cells travel efficiently to targets as they upregulate adhesion molecules and chemoattractant receptors.

13 Lymphocytes. Antigen-experienced T cells travel efficiently to targets as they upregulate adhesion molecules and chemoattractant receptors. T and B lymphocytes: Antigen-activated (via macrophages and dendritic cells) Release macrophage activating cytokines (in turn macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed) Plasma cells terminally differentiated B cells Express MHC molecules enable recognition of epitopes of antigens that discriminate self from non-self.

14 Mediators of Acute Inflammation Cell derived Histamine. (Mast cells, basophils, eosinophils. platelets) Stimulated by complement C3a and C5a, Iysosomal proteins Serotonin. Mast cells and platelets is vasoconstrictor. Lysosomal cmpds. (neutrophils) increases vascular permeability Prostaglandins. Inflammatory cells, increases vascular permeability Leukotrienes Lipidic acids also synthesized with vasoactive properties.

15 RESOLUTION OF INFLAMMATION. Acute inflammation early characterized by extravascular accumulation of neutrophils and edema formation. Later mononuclear cells and macrophages accumulate. Examination of the time course emphasizes that the process is normally resolved over time what processes terminate/reverse the inflammatory cascades..?

16 WHAT INITATES THE RESOLUTION OF ACUTE INFLAMMATION? REMOVAL OF STIMULUS Clearance of bacterial / viral components Clearance of injury products

17 MEDIATORS OF INFLAMMATION RESOLUTION. Early phase: inflammatory mediators initiate acute-phase. Counterbalanced by endogenous anti-inflammatory signals(corticosterone). As inflammation progresses, stop signals attenuate leukocyte traffic and promote differentiation of monocyte to phagocytosing macrophage (lipoxins, Resolvins, and PG-D) Fibroblasts evoke withdrawal of survival signals allowing leukocytes to undergo apoptosis or be cleared by lymphatics.

18 INFLAMMATION Inflammation in itself is not to be considered as a disease, but as a salutary operation consequent to some violence or some disease. John Hunter Scottish surgeon, 1794

19 BENEFITS OF INFLAMMATION Dilution of toxins. carried away in lymphatics. Entry of antibodies. Increased vascular permeability. Fibrin formation. Fibrin formation from exuded fibrinogen impede movement of micro-organisms Delivery of nutrients and oxygen. Delivery of nutrients and oxygen for neutrophils Stimulation of immune response. Drainage into the lymphatics allows particulate and soluble antigens to reach Iymph nodes.

20 HARM OF INFLAMMATION The release of by inflammatory cells may also have harmful effects: Digestion of normal tissues: lysosomal enzymes Swelling: obstruct airway, cranial cavity. Inappropriate inflammatory response: (e.g. hay fever)

21 Progression to Chronic Inflammation Progression to chronic stage. Cellular exudate changes: macrophages, lymphocytes and plasma cells replace neutrophils. Tissue destruction (necrosis) Attempts at reconstructing the damaged tissue (healing/ repair): granulomatous response

22 CHRONIC INFLAMMATORY STATES. Persistent Injury or inflammation Ulcer, TB, Ulcerative colitis, Inflammatory bowel disease, Atheroclerosis Prolonged toxic agent exposure Silicosis, foreign body Autoimmune disease states Rheumatoid arthritis, Multiple sclerosis

23 Important classes of agents used clinically in modulating the inflammatory process NSAIDS Steroids Cytokine blocking agents TNFa IL1ß

24 NSAID (Non Steroidal Anti-inflammatory drug): Common properties of action NSAIDs inhibit cyclooxygenase (COX) COX forms PGs in periphery/ spinal cord PGs sensitize sensory nerve terminal to enhance pain transmission(hyperalgesia). Block COX inflammation/hyperalgesia COX1 constitutively expressed throughout (GI mucosa, Platelets, kidney, etc) COX2. Expressed in brain and kidney and induced at site of injury Classical agents block both, while recent agents are COX2-selective.

25 CYCLOOXYGENASE 2 distinct active catalytic sites on COX Cyclooxygenase active site (CAS) (AA PGG2) and the peroxidase active site (PAS) (PGG2 PGH2). PGH2 may then be acted upon by various enzymes to yield multiple prostanoids

CYCLOOXYGENASE 1 and 2 COX 1 is stably expressed in brain and periphery COX2 is stably expressed in brain and but not periphery upregulated by a variety of stimuli: Bacterial endotoxin, IL-1, and

26 CYCLOOXYGENASE 1 and 2 COX 1 is stably expressed in brain and periphery COX2 is stably expressed in brain and but not periphery upregulated by a variety of stimuli: Bacterial endotoxin, IL-1, and TNF-a Cytokines (IL1ß) stabilizes COX-2 transcripts. Cortisol and dexamethasone NEGATIVELY controls COX2 transcription. Distinct binding pocket permits synthesis of COX2 preferring molecules Ibuprofen: COX1 = COX2 Celebrex: COX2>>COX1 Thus COX 2 inhibitors will be effective where there is ongoing inflammation leading to upregualtion of COX2.

28 2) 알레르기 (allergy) 무해한외래물질이나자가물질을외부감염원으로인식하여일어나는면역반응 산업화가진행됨에따라환경오염및식습관의변화등에의해알레르기환자의증가 T 림프구에의해항원이인식되면기억 B 세포가자극을받고항체를생산 알레르기증상환자는과잉면역반응이일어남 무해한항원에대한반응성이점점커져더격렬한면역반응이일어남

29 Genes Identified to date in Atopy

31 Common allergens associated with type I hypersenstivity Proteins Foreign serum Vaccines Plant pollens Rye grass Ragweed Timothy grass Birch trees Drugs Penicillin Sulfonamides Local anethetics Salicylates Foods Nuts Seafood Eggs Peas, beans Milk Insect products Bee venom Wasp venom Ant venom Cockroach calyx Dust mites Mold spores Animal hair and dander

33 Mast Cell Mast cell are abundant in the mucosa of the respiratory, gastrointestinal tracts and in the skin, where atopic reaction localize. Mast cell release mediator cause the pathophysiology of the immediate and late phases of atopic diseases.

34 Mast Cell Activation

35 Mast cell Minutes Classic Allergic Reaction Flushing Hypotension Increased mucus production Pruritus Smooth muscle contraction Vascular leakage Hours Late phase Reaction Eosinophil infiltration Neutrophil infiltration Fibrin deposition Mononuclear infiltration Tissue destruction

36 Performed Mediators/ Primary Mediators Histamine: is one well-known mediator. This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause: contraction of smooth muscles of the airway and GI tract, increased vascular permeability and vasodilation, nasal mucus production, airway mucus production, pruritus, cutaneous vasodilation, and gastric acid secretion. Serotonin: increased vascular permeability and contraction of smooth Muscles. Tryptase: is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a. Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation. Proteoglycans: include heparin and chondroitin sulfate. Chemotactic factors

38 Important Clinical Aspects of Immediate Hypersensitivity Main organ Disease Main sympto ms Lung Asthma Wheezing, dys pnea, tachypne a Nose and Eyes Skin Rhinitis, conjunctivitis Hay fever Eczema (atopic derm atitis) Urticaria Runny nose, re dness and itchi ng of eyes Pruritic, vesicul ar lesions Pruritic, bullous lesions Typical allergen s Pollens, house d ust, animal dande rs Pollens Uncertain Various foods Drugs Route of entery Inhalation Contact with muc ous membrane Uncertain Ingestion Various Intestinal tract Allergic gastroentero pathy Vomiting diarrh ea Systemic Anaphylaxis Shock, hypoten sion, wheezing Various food Insect venom;bee Drugs; penicillin Foods; Peanuts Ingestion Sting Various Ingestion

39 2. 기능성평가방법 1) 시험관내실험수준 히스타민및헥소사이니데이스 T 세포증식리폭시제네이즈생성량사이토카인생성량 2) 동물실험수준 전신성알레르기반응, 국소성알레르기반응 (PCA) 히스타민과염증성사이토카인및 IgE 함량귀부종법족척두께증가 3) 임상시험 단자시험 (prick test) 혈액중히스타민함량혈액중 IgE 혈중사이토카인함량

42 3. 항염증및항알레르기건강기능식품 1) 개별인정형건강기능식품 (1)Enterococcus faecalis FK-23 효소및가열처리분말 Th2 매개면역을 Th1 매개면역방향으로전환시키는효능 코막힘증상을개선하는데도움을줄수있음

43 Skin Tests The cutaneous test (prick test, puncture test epicutaneous test) Routine diagnosis in diseases (atopic or anaphylactic). A single drop of concentrated aqueous allergen extract placed on the skin which is then pricked lightly with a needle point at the center of the drop. After 20 minutes the reaction is graded and recorded

44 Reference Funtional food 이형주외수학사 Allergic diseases: in Medical Immunology.eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), 814 pages tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) (March 23, ISBN-13: ISBN-10: Anaphylaxis and Urticaria: in Medical Immunology.eds ( Tristram G.Parslow, Daniel P. A Stites, Abba I.Terr.and John B. Imboden), 814 pages tenth edition. McGraw-Hill/Appleton & Lange; 10 edition 2001) (March 23, ISBN-13: ISBN-10: Adkinson NF Jr. Middleton s Allergy: Principles and Practice. 6th ed. Philadelphia, Pa: Mosby; Rakel RE. Textbook of Family Medicine. 7th ed. Philadelphia, Pa: WB Saunders; Miriam K Anand, Michael A Kaliner, et al., Advances in Immunology. N Engl. J.Med,. vol. 344, No.1. January4, Available from. Sell S, Rich RR, Fleisher TA, et al, eds. Clinical Immunology: Principles and Practice. ed. St. Louis, Mo: Mosby-Year Book; 1996:449-77

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ÀÇÇÐ°�ÁÂc00Ì»óÀÏ˘ Common Allergic Diseases in Children Sang - Il Lee, M.D. Department of pediatrics Sungkyunkwan University School of Medicine, Samsung Medical Center E - mail : silee@smc.samsung.co.kr Abstract Allergy